In this revised application, we addressed the IRG's concerns: we clarified the number/type of assessments on the 3 subject groups; proposed a further Hypothesis that mirrors better the use of childhood archival data about probands and their sibs; added ICAM-1 to our biological markers; and responded to various other concerns. Our study focuses on depression and coronary heart disease (CHD), which are enormous public health problems across the world. Depression not only predicts new onset CHD, and morbidity, and mortality in those with existing CHD but also is associated with behavioral risk factors (e.g. smoking, being sedentary) for eventual CHD. Although the depression-CHD link is well established, the causal role of depression is still being debated, and its most cardiotoxic features are yet to be confirmed. Notably, although both depression and CHD often originate in the pre-adult years, few studies have examined their association with behavioral CHD risk factors in a developmental context. We propose to assess 3 established samples of young adults in Hungary: a) probands (n=325), whom we have followed since childhood, when they had their first episode of major depression around the mean age of 9 years, b) never-depressed siblings of probands (n=325), and c) normal peer controls (n=155). We recently reported that: a) proband families have elevated rates of parental CV disease, b) by adolescence (mean age=17 years), being a proband predicted increased rates of behavioral risk factors for CHD (e.g., smoking, being sedentary), and c) rates of behavioral risk factors were highest among probands, lowest among controls, and intermediate among never depressed siblings of probands. The goal of the proposed study is to assess, for the first time, traditional biological risk factors (e.g., LDL cholesterol, blood pressure), along with behavioral risk factors, and several markers of CHD risk: pulse wave velocity, interleukin-6 and C-reactive protein (inflammation), ICAM-1 (endothelial function), and the metabolic syndrome. Our hypotheses address the levels of CHD risk markers as a function of subject group, the role of behavioral risk factors in adolescence in the link between depression and preclinical physiological outcomes, the impact of developmental trajectories of stress and risk variables on physiological outcomes among probands-sibs, and the most cardiotoxic clinical features of depression. Our extensive archival data on subjects' psychiatric history, family stress events, parental history of cardiovascular disease, socio-demographic variables, and various behavioral risk factors for CHD will yield a unique characterization of the unfolding relationships among depression, behavioral risk factors, and early markers of CHD risk. The sibling design will help isolate the contribution of depression to early markers of CHD risk by controlling for the adverse health impact of several family-based variables. Given the public health burden posed by depression and CHD, their study in young adults is particularly warranted, because risk factors and/or preclinical signs of CHD risk may be easier to modify earlier, rather than later, in the lifespan.